Basal cell carcinoma (BCC) is the most common skin cancer, with a rapidly growing prevalence in countries with majority white populations. Even though a number of treatment strategies exist, only surgery and topical treatments provide an optimal outcome.
Keratinocyte carcinomas (KCs) such as BCC and squamous cell carcinoma (SCC) are by far the most common malignancies worldwide and exceed prevalence of all other cancers combined. The incidence of BCC is rising by around 10% each year in white populations, such as those living in Australia, yet poor registration of BCC makes it difficult to compare estimates across the world.
A large US gender-stratified cohort study showed age-adjusted BCC incidence rate increases from 519 cases to 1,019 cases per 100,000 person-years in women and from 606 cases to 1,488 cases per 100,000 person-years in men. Similar rising incidence rates have been discovered in Europe, Canada, Asia, and Australia.
There are different histopathological subtypes of BCC, based on the growth patterns found within the tumour tissue. Although nodular BCC is the most common subtype, superficial BCC accounts for 10% to 17% of all BCCs and up to 38% of BCCs in certain locations, such as the neck. Patients with a superficial BCC more often have their BCC on the trunk and extremities than in the head and neck region, are younger and more often female.
Trends toward aging populations mean that the supply of appropriate treatment such as excisional surgery may be stretched in state-run health care systems, and it has been estimated that the number of patients presenting to dermatologists will increase by 50% by 2030. Such a trend has resulted in guidance for more family practitioners to provide treatment for low-risk lesions in the community.
In addition, the disability‐adjusted life years and healthcare costs for BCC have risen significantly as well. This is cause for concern, since considerable morbidity may result from the local aggressive nature of BCC and BCC recurrences.
Male gender and age remain the most common overall independent risk factors for the development of BCC. Patients with an initial truncal superficial BCC developed metachronous BCCs at a faster rate than patients with other anatomical site and histology combinations.
A majority of evidence suggests that intermittent sun exposure (i.e. recreational tanning, occupational exposure, childhood sunburns) is a predominant risk factor, while chronic cumulative sun exposure may not play the critical role it does in SCC carcinogenesis. A 20-year observational study involving 73,494 female nurses showed a strong dose-related association between tanning bed use and skin cancer risk; this association was stronger for patients with younger age of exposure and most significant for BCC. Evidence also appears to suggest that sBCCs are also more common in patients with multiple prior BCCs.
Skin pigmentation’s protective role from carcinogenesis is exemplified by low incidence rates in individuals of African descent.
Large epidemiological studies have shown that ionising radiation increases BCC risk in area of treatment; younger age at time of radiation may increase this association. A population-based, case-control study conducted in Alberta, Canada, revealed an increased risk with recreational sun exposure in childhood and adolescence, suggesting that these life periods may be critical for establishing adult risk for BCC.
Oral contraceptive use may also be associated with increased risk and more aggressive subtypes, potentially helping explain recent data showing a higher rate of incidence increase in women. Women also tend to use tanning beds more often than men and pay closer attention to their health and physical appearance than men do, which may lead to more medical visits.
The main strategy to reduce the risk of BCC appears to be protection from UV exposure, especially in childhood and adolescence. Behaviorally, this means avoiding sunburns, tanning beds, and prolonged direct sun exposure between 10 a.m. and 4 p.m., as well as wearing protective clothing, such as wide-brimmed hats and long-sleeved shirts, while outdoors during the day. While the benefit of applying sunscreen in the prevention of BCCs is unclear, a mathematical model based on epidemiological data estimated that the regular use of sunscreen with SPF of 15 during the first 18 years of life would reduce the lifetime incidence of BCC by 78 percent.
Superficial BCCs classically present as a well circumscribed and erythematous thin plaque or patch with scale, central clearing, and thin rolled borders. Its major histopathological features are multiple lobular foci of basaloid palisading keratinocyte tumors attached superficially to the epidermis with a myxoid stroma and bandlike lichenoid infiltrate.
They can sometimes be mistaken for inflammatory lesions, as well as SCC in-situ. On histopathology, superficial BCCs demonstrate multiple lobular foci of basaloid palisading keratinocyte tumors attached superficially to epidermis with a myxoid stroma and band-like lichenoid infiltrate.
Nearly all BCCs show constitutive activation of Hedgehog signaling pathway (Hh), and several animal models have shown that amplified Hh is alone sufficient for tumorigenesis. Intermittent intense sun exposure is significantly associated with BCC development via UV-driven mutagenesis and is exacerbated by fair skin, red or blond hair, light eye color, and inability to tan.
After visually inspecting a lesion in search of characteristic features of BCC, clinicians can rely on dermatoscopy to further refine the differential diagnosis. Dermatoscopy, or the use of a magnifying device that emits polarized light to examine the skin, can detect reliable and robust diagnostic parameters, including arborizing telangiectasias, leaflike areas, foci of microulceration, multiple blue/gray globules, and large blue/gray ovoid nests.
No suspected lesion should be treated without histopathologic confirmation. Various biopsy techniques may be used, including excisional, incisional, shave, and punch biopsies. Punch and shave biopsies have been shown to have similar diagnostic accuracy. Even so, in most patients, the preferred biopsy method is a shave biopsy that incorporates the full depth of the lesion.
Superficial BCC is confined to or contiguous with the epidermis, and because of this lack of deeper invasion is usually treated with a variety of destructive modalities, such as cryotherapy or electrodesiccation and curettage, that may yield cure rates for BCC of greater than 90%. Hypopigmentation or atrophic scarring are common sequelae of these modes of treatment because of nonselective injury to surrounding healthy tissue. Other methods of treatment, such as surgery or radiotherapy, may also produce visible scarring.
Certain studies indicate that potentially noninvasive imaging techniques, such as optical coherence tomography (OCT), may be useful to diagnose and manage patients with sBCC and obviate the need for biopsy. However, careful follow‐up is required in such cases as there is a small risk (5%) of misdiagnosis.
A high cure rate is a key goal for clinicians; however, multiple other aspects should be considered when evaluating sBCC treatments, such as side effects and complications, patient preferences and treatment cost. The goal of treatment of sBCC is to completely remove the tumour and maximally preserve function and cosmesis at the site of treatment. Choice of treatment depends in large part on the risk of lesion recurrence, which in turn depends on the presence or absence of aggressive clinical and histopathologic features.
Another important consideration for treatment choice is location of the lesion, as preservation of function and cosmesis is paramount in certain locations, such as the face. Accurate assessment of a lesion’s risk for recurrence and selection of appropriate management is important to avoid overtreatment of low-risk lesions and under-treatment of high-risk lesions. Patient preference after a discussion of the risks and benefits of various modalities is also an important consideration in treatment selection.
While most BCC subtypes require surgery, sBCC can safely be treated topically with alternatives such as photodynamic therapy (PDT), imiquimod cream, fluorouracil cream, cryosurgery, or electrodessication and curettage. The main advantages of non-invasive treatments like PDT, imiquimod and flourouracil are good cosmetic outcome, preservation of surounding tissue and the potential for home application of both creams.
Topical imiquimod 5% cream is approved by the FDA for the treatment of superficial BCCs in low-risk sites. A recent study by Jansen et al reported the results of a 5-year randomized trial that measured the efficacy of topical imiquimod, topical 5-fluorouracil (5-FU), and methyl aminovulinate photodynamic therapy (MAL-PDT) in treating superficial basal cell carcinoma (sBCC). Although the 3-year results from the same trial found that imiquimod was more effective than MAL-PDT, the 5-year analyses are now able to conclude that imiquimod is also superior to 5-FU in preventing sBCC recurrence.
This particular study focused on sBCC because it has a relatively high incidence and is the only subtype of basal cell carcinoma approved for treatment with both imiquimod and 5-FU. Both imiquimod and 5-FU produce substantial side effects including local skin reactions such as itching, burning, pain, and erythema.
Despite the potential for local adverse reactions, a recent study demonstrated that patients prefer topical imiquimod over surgery for sBCC treatment. A number of studies using patient surveys have also shown that patients value the effectiveness of a treatment and cosmetic results over the potential risk for side effects. However, it is notable that treatment preferences appear to be influenced by the patients’ previous treatments, such that patients value characteristics of the treatment methods they have received in the past.
Imiquimod and 5-FU have very different mechanisms of action. Imiquimod is thought to work by stimulation of Toll-like receptor 7, subsequently activating the innate immune system. In contrast, 5-FU is believed to work by inhibiting thymidylate synthetase as well as by additional mechanisms that both interfere with DNA synthesis in replicating cells and cause DNA damage.
It appears that, in the long term, the immune-modulating mechanism of imiquimod may produce longer clinical efficacy after treatment. In this regard, a study of actinic keratosis treatment found that although imiquimod had a poorer initial clearance rate as compared with 5-FU, by 1 year it showed better sustained clearance. Another long-term concern of 5-FU treatment is that it may ultimately alter the biological behaviour of BCC from a simple to a more difficult to treat lesion such as a morphoeic BCC.
In the SINS randomised controlled trial, participants were randomised to imiquimod 5% cream once daily or excisional surgery (4-mm margin). It found that, while surgery was more effective at clearing sBCCs, imiquimod’s overall success rate of 82.5% at 5 years still represents a useful clinical response, especially because most treatment failures are identified early, and long-term responses seem to be maintained.
Additionally, recurrences of low-risk BCC treated with topical imiquimod did not appear to be difficult to treat, suggesting that a possible future strategy to deal with the epidemic of BCC might be to treat low-risk BCC in the community using imiquimod and to deal with recurrences surgically.
The few treatment failures with topical imiquimod that did occur, did so in the first year of treatment, a finding that throws light on the possible mechanisms of topical immunotherapy for skin cancer, suggesting that once an immunological response has occurred, such a response is sustained.
Pooled results of two identical multicenter randomized phase III trials proved the efficacy of imiquimod for the treatment of superficial BCC. Treatment with topical imiquimod 5% cream once daily, five times per week for 6 weeks resulted in a histologic clearance rate of 82 percent 12 weeks after treatment.
Topical imiquimod appears to be less effective for the treatment of nodular BCCs. A randomized phase III trial showed that thrice-weekly topical imiquimod for either 8 or 12 weeks for the treatment of low-risk nodular BCC resulted in complete histopathological clearance upon subsequent surgical excision of the lesion and margin evaluation in only 64 percent of tumours. This rate of efficacy demonstrates why imiquimod has replaced 5-FU as the first line therapy for the treatment of sBCCs.
While there are many possible treatments for the occurrence of BCCs, and sBCCs in particular, surgery and imiquimod 5% appear to be the most effective modes of therapy. An optimum approach to the treatment of sBCCs is to take the patient’s wishes regarding cosmetic outcomes into account and either proceed with imiquimod therapy or use surgery to supplement imiquimod 5% therapy in the event of recurrence.